Aminoalkoxy-tetrahydro-cyclopropa {8 b{9 naphthalenes

ABSTRACT

Compounds are provided having the structure   These compounds are useful as antiparasitic agents, antibacterial agents, and anti-inflammatory agents as well as surfact active agents.

United States Patent [191 Narayanan 1 Dec. 2, 1975 1 AMlNOALKOXY-TETRAHYDRO- CYCLOPROPA [BlNAPHTHALENES [75] Inventor: Venkatachala L. Narayanan,

Hightstown, NJ.

[73] Assignee: E. R. Squibb & Sons, Inc.,

Princeton, NJ.

22 Filed: Dec. 17, 1973 21 Appl. No.: 425,413

Related US. Application Data [62] Division of Ser. No. 252,814, May 12, 1972, Pat. No.

3,796,760, which is a division of Ser. No. 73,668, Sept. 18, 1970, Pat. No. 3,694,512.

[51] Int. Cl. C07C 93/06 [58] Field of Search 260/501.18, 501.19, 343.7, 260/570.7

[56] References Cited UNITED STATES PATENTS 3,694,512 9/1972 Narayanan 260/570.7 X

Primary ExaminerR. V. Hines Attorney, Agent, or FirmLawrence S. Levinson; Merle J. Smith; Donald J. Barrack [57] ABSTRACT Compounds are provided having the structure These compounds are useful as antiparasitic agents. antibacterial agents, and anti-inflammatory agents as well as surfact active agents.

2 Claims, N0 Drawings AMINOALKOXY-TETRAHYDRO-CYCLOPROPA [BINAPHTHALENES This is a division of US. patent application Ser. No.

252,814, filed May 12,1972, now US. Pat. No. 5

The present invention relates to tetrahydro-cyclopropa[b]naphthalenes of the structure wherein R is hydrogen, lower alkyl, lower alkoxy, or cycloalkyl; R and R are the same or different andcan be hydrogen, lower alkyl or lower alkoxy, R and R are the same or different and can be hydrogen, chlorine or bromine, although at least one of R and R is chlorine or bromine; R is hydrogen, lower alkyl, aralkyl or (CH CO R where m=l to 10, and R is hydrogen, lower alkyl, or aralkyl. Furthermore, R can be aminoalkyl having the structure -(CH ),,NR R wherein n is 2 to 6, R and R can be the same or different and represent hydrogen, lower alkyl, aralkyl, monocyclic cycloalkyl, monocyclic aryl or hydroxy-lower alkyl and R and R can be taken together with the nitrogen to form a 5 to 7 membered monocyclic heterocyclic ring.

The term lower alkyl as employed herein includes both straight and branched chain radicals of up to and including eight carbon atoms, for instance, methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl and the like. The lower alkyl group can include substituents such as aryl.

The term lower alkoxy includes straight and branched chain lower alkyl groups attached to an oxygen.

The term monocyclic aryl as employed herein includes monocyclic carbocyclic aryl radicals, for instance, phenyl and substituted phenyl radicals, including lower alkyl phenyl, such as tolyl, ethylphenyl, butylphenyl and the like, di(lower alkyl)phenyl (e.g., dimethylphenyl, 3,5-diethylphenyl and the like), halophenyl (e.g., chlorophenyl, bromophenyl, and 2,4,6-trichlorophenyl) and nitrophenyl.

The term monocyclic cycloalkyl includes cyclic radicals containing from 3 to 6 ring members (e.g., cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl).

The radicals (CH and -(Cl-l encompass straight chain or branched bivalent lower alkyl groups,

Examples of the basic nitrogen containing radical symbolized by the group include amino, lower alkylamino, e.g., methylamino, ethylamino; di(lower alkyl )amino, e.g., dimethylamino, diethylamino, dipropylamino; (hydroxy-lower alkyl- )amino, e.g., B-hydroxyethylamino; di(hydroxy-lower 2 alkyl)amino, e.g., di(hydroxyethyUamino; phenyl(- lower alkyl)amino, e.g., benzylamino, and phenethylamino.

As indicated above, the nitrogen may join with the groups represented by R and R to form a 5 to 7 membered monocyclic heterocyclic containing, if desired. an oxygen, sulfur or an additional nitrogen atom, (not more than two hetero atoms altogether), that is, the two symbols R and R represent together tetramethyl- U ene, pentamethylene, hexamethylene, oxapentamethylene, oxatetramethylene, azahexamethylene, azapentamethylene, azatetramethylene, thiapentamethylene or thiatetramethylene. The heterocyclic group may also be substituted by one or two groups represented by Illustrative heterocyclic groups include piperidino, e.g., methylpiperidino, di(lower alkyl)piperidino, e.g.. dimethylpiperidino, (lower alkoxy)piperidino, e.g., methoxypiperidino, pyrrolidino, (lower alkyl)pyrrolidino, e.g., 2-methylpyrrolidino, di(lower alkyl)pyrrolidino, e.g., 2,5-dimethylpyrrolidino, (lower alkoxy)pyrrolidino, e.g., ethoxypyrrolidino, morpholino, (lower alkyl)morpholino, e.g., 3-methylmorpholino or 2- methylmorpholino, di(lower alkyl)morpholino, e.g., 2,3-dimethylmorpholino, (lower alkoxy)morpholino, e.g., 2- or 3-ethoxymorpholino, thiarnorpholino. (lower alkyl)thiamorpholino, e.g., Z-methylthiamorpholino or Z-methylthiamorpholino, di(lower alkyl)thiamorpholino, e.g., 2,3-diethylthiamorpholino or 2,3-dimethylthiamorpholino, (lower alkoxy)thiamorpholino, e.g., Z-methoxythiamorpholino, piperazino, (lower alkyl)piperazino, e.g., 4-methylpiperazino, Z-methylpiperazino, di(lower alkyl)piperazino, -e.g., 2,3-dimethylpiperazino, hydroxy-lower alkylpiperazino, e.g., 4- (2-hydroxyethyl)piperazino, hexamethyleneimino and homopiperazino.

Preferred are those compounds wherein R and/or R are chlorine, R and R are hydrogen. R is hydrogen or methyl, and R is hydrogen, methyl or benzyl.

Examples of compounds falling within the present invention include, but are not limited to, the following:

18. BI ci o (c21 -K (CH -N N-CH CH OH Compounds of formula I can be prepared by the Birch reduction of a naphthol of the structure i.e., by reducing the naphthol II with an alkali metal such as lithium or sodium, in a molar ratio of naphthol to alkali metal of within the range of from about 1:2 to about 1:50 and preferably from about 1:10 to about 1:20 in the presence of liquid ammonia, a proton SOUI'CQSUCh as a lower alkanol, for example ethanol, and ethyl ether to give a 5,8-dihydronaphthol of the structure The 5,8-dihydronaphthol is reacted with a halide of the structure which is reacted with a halocarbene of the structure VI :CR R' in a molar ratio of VzVl of within the range of from about 01:1 to about 1.5: l at a temperature within the range of from about 0 to about C, to form a compound of structure I.

As an alternate approach. a'compound of formula V wherein R is benzyl is first reacted with a halocarbene of structure :CRR under the conditions specified above to give a compound of formula I where R is benzyl i.e.,

Q R &

VII

R 4 I R The compound of formula Vll is then debenzylated using 540% palladium/carbon as catalyst in a solvent like ethyl alcohol to give a compound of formula I wherein R is H VIII The compound of formula VIII is then reacted with R X (R other than hydrogen) to give compound of general structure I.

The above alternate method is specially suited to the synthesisof materials wherein the R substituent is sensitive to the conditions of the halocarbene addition step mentioned previously.

The solvents used for the above reactions may vary and include methyl and ethyl alcohols, tetrahydrofuran, dimethylformamide. benzene. toluene. dimethoxyethane, etc.

Examples of naphthol starting materials include the following:

OH l

CrI

CH O

OCH

-CH CH 3 OH (1 H I 7-.

CH O

8 The halide includes halides such as alkyl halides, for example methyl iodide, ethyl chloride, propyl bromide, benzyl chloride, as well'as halides of the structure Examples of halides of the structure Vlll Hal- (CH ),,NR R Vlll suitable for use in preparing compounds of the invention include the following: dimethylaminoethyl chloride. dimethylaminopropyl chloride, methylethylaminomethyl bromide, ethyl-i-propylaminobutyl iodide, methylaminoethyl chloride, aminopropyl bromide, methylbenzylaminopentyl chloride, cyclohexylaminoethyl bromide, hydroxyethylaminohexyl iodide, hydroxyethoxyethylaminopropyl chloride, pyr rolidinoethyl chloride, piperidinopropyl iodide, piperazinobutyl chloride, morpholinopentyl bromide, thiamorpholinohexyl iodide as well as alkylene halides containing substituted heterocyclics as indicated hereinbefore.

Halocarbenes may be generated under basic conditions either by (a) reaction of a haloform or ethyltrihaloacetate with a base like potassium hydroxide or potassium-t-butoxide; or (b) reaction of a polyhalide with an alkyl lithium. Halocarbenes may be generated under non-basic conditions by the decomposition of phenylhalomethylmercury.

Compounds of formula I where R is hydrogen may be conveniently prepared from compounds of formula I where R,-, is benzyl, by hydrogenolysis using palladium on charcoal or other known catalyst for reduction.

The compounds of formula I wherein the side chain has a basic amino function form physiologically acceptable acid-addition salts with inorganic and organic acids. These acid-additionsalts frequently provide useful means for isolating the products from reaction mixtures by forming the salt in a medium in which it is insoluble. The free base inay then be obtained by neutralization, e.g., with a base such as sodium hydroxide.

Then any other salt may again be formed from the free base and the appropriate inorganic or organic acid. lllustr'ative are the hydrohalides,'especially the hydrochloride and hydrobromide which are preferred, sulfate, nitrate, phosphate, oxalate, tartrate, maleate, fumarate, pamoate, citrate, succinate, benzoate, ascorbate, methanesulfonate, benzenesulfonat'e, toluenesulfonate, and the like.

The compounds of this invention can be. utilized as parasiticides and rodenticides, being particularly useful against Hymenolepis nana, -Nematospiroides ,zlubius, Nippostrongvlus brasiliensis.,and Asca ris lumbric'oides. These compounds when utilized as parasiticides form the active ingredient in feed stuffs for cattle, hogs and chickens, being admixed with, said feed stock in from 0.] to 25 mg. per 100 kg weight of feed stuffs with the most preferred range being from about to mg. per kg. of feed stuffs. y I

As anti-inflammatory. agents, the compounds of this invention may be used topically and/or orally in lieu of and in the same manner as cortisone in the treatment of acute inflammatory and allergic conditions of the eye, skin or mucose, e.g., as suspension, ointment or cream containing about 0.], to about 2.5% by weight, of a compound of formula I or physiologically acceptable salt thereof. In the rabbit or cow, for example, a 1%.

ointment is applied to the skin area 3 to 4 times daily. Furthermore, the new compounds of formula I are useful as antimicrobial agents and may be used to combat infections in animal species, such as mice, rats, dogs, guinea pigs and the like, due to organisms such as Trichamonas raginalis, Trichomonas foetus, Staphylococcus aui'eus, Salmonella schottmuelleri, Klebsiella pneunzonz'ae, Proteusrulgdris, Escherichia coli, C. albicans or Tricliophyton mentgqrup/rrtes. For example, a compound or mixture ofdcompounds of formula I or physiologically acceptable acid addition salts as defined hereinbefore may be administered orally to an infected animal, e.g., to a mouse, in an amount of about 5 to mg. per day in 2 to 4 divided doses. These may be conventionally formulated in a tablet, capsule or elixir containing about 10 to 250 mg. per dosage unit, by compounding the active substance or substances with the conventional excipient, vehicle, binder, preservative, flavor, etc., as called for by accepted pharmaceutical practice. They may also be applied topically, e.g., to dermatophytosis in a guinea pig, in a lotion, salve or cream at a concentration of about 0.01 to 3 percent by weight.

They may also be used as surface disinfectants. About 0.01 to 1 percent by weight of any of these substances may be dispersed on an inert solid or in a liquid such as water and applied as a dust or spray. They may be incorporated also, for example, in a soap or other cleansing agent, e.g., a solid or liquid detergent, detergent composition, for example, in general cleaning, in cleaning dairy barns or equipment or cleaning food handling or processing equipment.

The following examples are illustrative of the invention. All temperatures are on the centigrade scale.

EXAMPLE 1 cyclopropa [b]naphthalene A. 5,8-Dihydro-l-naphthol I A 3-1. three-necked flask, equipped with a dry condenser, a sealed Hershberg-type stirrer, and an inlet monia as rapidly as possible (about 5 minutes). When the naphthol has goneinto solution (about l0 minutes), 208g (3.0g atoms) of lithium metal is added in small pieces and at such a, rate as to prevent the ammonia from refluxing too violently. Afterthe addition of the lithium has been completed (about45 minutes),

the solution is stirred for an additional 20 minutes and is then treated with 170 ml (3.0 mole) of absolute ethanol which is added-dropwise over a period of 3045 minutes. The condenser is removed, stirring is continued, and the ammonia is evaporated in. a stream of air.

introduced through the inlet tube. The residue is dissolved in l l. of water, and after the solution has been extracted with two ml portions of ether, it is carefully acidified with concentrated hydrochloric. acid. The product formed is taken into ether with three 250 ml extracts, and then the ether extract is washed with water and dried over anhydrous sodium sulfate. The ether is removed by. evaporationto yield l06l08g (97-99%) of crude 5,8-dihydrol naphthol, mp 697l. This material is dissolved in benzene, treated with charcoal, concentrated and crystallized to give pure 5,8-dihydro-l-naphthol, mp 70.5" 72.

B. 5,8-Dihydrol -naphthol, benzyl ,ether Method 1. A mixture of 29.2g (02 mole) of 5,8-dihy- =dro-l-naphthol, 28.0g (0.2 mole) of anhydrous K CO 37.69g (0.22 mole) of benzyl bromide and 200 ml of dry acetone is stirred and refluxed for l2.hours. The solvent is removed in vacuo, the residue is mixed with 200 ml of water, and extracted with ether. The ether extract is washed with water, dried (MgSO and cvaporated to give 40g of oil, which solidifies on standing. A sample crystallized from 'pentane. melts .at 69-72.

Method 2. To a cooled-solution of 219g (0.15 mole) of 5,8-dihydro-l-naphthol in 100 ml of anhydrous ethanol, 7.29g (0.15 mole) of 50% sodium hydride is added in portions. After the evolution of hydrogen has ceased, 25.6g (0.15 mole) of benzyl bromide is added dropwise, and the mixture refluxed with stirring for 12 hours. The solvent isremoved in vacuo, the residue is mixed with 200 ml of ,water and extracted with chloroform. The chloroform extract is washed with water, dried (MgSO and evaporated to give 33.5g (94%) of brown solid. It is dissolved in ether-pentane, decolorized with Darco, dried (MgSO and evaporated to give 30g of product, identical to that obtained by Method I C. 3-(Benzyloxy)-l l -dichloro-la,2,7,7a-tetrahydrolH-cyclopropa [b]naphthalene Method 1. A solution of 10g (0.042m) of benzyl ether of dihydro naphthol, in ml of benzene and 1] g of potassium t-butoxide are placed in a threenecked flask equipped with a N inlet, dropping funnel and magnetic stirrer. The flask is cooled in an ice bath while ll.8g of CHCL, is added dropwise; the mixture turns dark. The temperature is maintained at about 25. After the addition, the mixture is stirred one-half hour at.room temperature. Then water is added to quench obtained. mp 748(). Recrystallization from methanol gives yellow crystals, mp 82-85, 1' CDCI singlet at 4.93 1' (-CH. of benzyl), 2.58-3.4 r (aromatic protons) 12 92.596.5, h,,,, 3450cmbroad OH. 1' CDCL; singlet at 5.25 r OH. 2.83.6 aromatic protons.

Anal. Calcd. for C H oCl z C,57.67; H.440; Cl,30.95. Found: C.57.72'. H.447; Cl.3().73.

Anal. Calcd. for C H OCb: C,67.73; H.506; 5 022.22. Found: C6778; H.524; 0.22.13. EXAMPLE 3 Method 2. To a solution of 2.3g (0.01 mole) of ben- 3 3- i m p -r g 7 7 zyl ether of dihydronaphthol in 300 ml of dry benzene. tetrahydro-lH-cyclopropa[b]naphthalene 3.9g (0.01 mole) of phenyl (trichloromethyl)mercury 7 is added. and the mixture refluxed for 48 hours. The 10 To a Cooled of (0'01 mole) product of Example 2 in ml of anhydrous ethanol 0.48g

precipitate (phenylmercurlc chloride) 15 filtered off, (0 01 moe) of 5017 sodium h 'dride is added in Or and the solution concd. to give a solid residue. The c y P 1 I I y trons. After the evolution of hydrogen has ceased, 1.5g SOlICl IS LllSSOh ed in methanol and allo ed to crystalllze i o o (0.01 mole) of Z-(drmethylammo) ethyl bromide is slowly. 0.7g, mp 82 -85 iridentical to the product obdd d d d h fl d h mined by Method (U 15 a e ropmse, an t e mixture IS re uxe wit stirring for 3 hours. The solvent 18 removed in vacuo, the EXAMPLE 2 residue is mixed with'25 ml of water and the mixture I H I extracted with chloroform. The chloroform extract is H Dlchloro i fgff l g H cyclopropdlb washed with water, dried (MgSO and concd. to give mp 3-lZ-(dimethylamino)ethoxyl-l.l-dichloro-la, 2,7,7a- A solution of 2g (0.006m) of product of Example I m tetrahydrol H-cyclopropa[b]naphthalene. 200 ml of ethanol and a slurry of lg of 10% Pd/C in 10 ml of 95% are placed in a Parr bottle and hydro- EXAMPLES 4 to 21 genated until the uptake of hydrogen ceases. The cataln a manner similar to that described in Examples 1, lyst is filtered off. the solvent is evaporated in vacuo. as 2 and 3, where the naphthol, halide (R X) and halocar- C HC I is added. dried (MgSO and solvent evaporated bene employed are as shown in columns I, 2 and 3 rein vacuo to give 1.3g (95%) of solid, mp 8993C. Respectively. of Table l below. the product shown in crystallization from hexane gives crystals. mp Table lV is obtained.

TABLE 1 Column 1 Column 2 Column 3 Column 4 RX :CR-"R R R R'-' x R- R" R R RR'-R"RR" 4 H CH3 H Cl C2H,-, Br Br H Same as in columns 4 H H (1H,, Br H Br Cl H LZand 3 a H ocH H l (CH-r).I Cl H H CH 7 H OC- -H H Cl (cH. .N Cl C] H cHfl s 2C"H H l cH. .co. ,C. .H Br H :t 7 9 1 C. .H. CHn Br CH5 Br Br -C H,,

ltl 4 oc. ,H,. H H Cl tCH .);.-N c|i-1 cH Cl e-oc2Hr c..H.oH ll H H H C! cH. fl-N Br Br H C. .H.0H

12 H H H Cl CH2CH- .CO. .H Cl Cl H Same as in columns l. 2 and 3 l3 2- C H C,H Br (CHM-NU Cl C] 4- Z u L Q H i C -,H Cl CH2 G H c1 5- Q What is claimed is: 1. Compounds of the structure wherein R is hydrogen, lower alkyl, lower alkoxy or cycloalkyl; R and R are the same or different and are hydrogen, lower alkyl or lower alkoxy; R and R are the same or different and are hydrogen, chlorine or brophenyl, lower alkylphenyl, di-lower alkylphenyl. chlorophenyl, bromophenyl, nitrophenyl or 2,4,6-trichlorophe nyl.

2. The compound in accordance with claim 1 3-[2- (dimethylamino )ethoxy l l -dichlorol a,2,7,7a-tetrahydro-l l-l-cyclopropa[b]naphthalene.

| UNITED STATES PATENT AND TRADEMARK OFFICE 0 QERTIFICATE OF CORRECTION PATENT NO. 3,923,890

DATED December 2, 1975 INVENTOR(S) Venkatachala L. Narayanan it is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Columns 13 and 14, Table 1, 53 should read:

15 Br 16 Cl 17 Br 4 l8 Br 19 Cl 20 Br 21 Cl Signed and Scaled thisthirtieth D f March 1976 [SEAL] Arrest:

t RUTH C. MASON C. MARSHALL DANN AIIPSII'HK Offl'fl Commissioner of Parents and Trademarks t t t 1 I I Signed and Scaled this- UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. 3,923,890

DATED December 2, 1975 INVENTOR(S) Venkatachala L. Narayanan It is certified that error appears in the aboveAdentified patent and that said Letters Patent are hereby corrected as shown below:

Columns 13 and 14, Table l, P should read:

15 Br 16 Cl 17 Br 18 Br 19 Cl 20 Br 21 Cl thirtieth D f March 1976 [SEAL] A Itest:

RUTH C. MASON C. MARSHALL DANN Arresting Officer Commissioner nj'Patents and Trademarks 

1. COMPOUNDS OF THE STRUCTURE
 2. The compound in accordance with claim 1 3-(2-(dimethylamino)ethoxy)-1,-1-dichloro-1a,2,7,7a-tetrahydro-1H -cyclopropa(b)naphthalene. 